ARSENIC DERIVATIVES OF DIPHENYLUREA
Oct. 5 , 1054
[CONTRIBUTION FROM
4929
ABBOTTLABORATORIES]
Arsenic Derivatives of Diphenylurea BY WAVERLY D. KRUEGER, LEROYW. CLEMENCE AND MARLIN T. LEFFLER~ RECEIVED APRIL29, 1954 A series of diphenylureas has been prepared, in which t h e aromatic rings were symmetrically substituted by arson0 and arsonoso substituents. Some of the compounds have shown activity against E. histolytica in vitro.
Pentavalent arsenic compounds such as carbarsone and acetarsone have been used in the treatment of amebiasis for many years. More recently, Anderson2 showed that the trivalent arsenic compounds (Type A)-carbarsone oxide and its thioglycolic acid and thiosalicylic acid derivatives-were active in human and monkey amebiasis. We have prepared this series of penta- and trivalent arsenic compounds of type B in which the nitrogen atoms of the ureido linkage were symmetrically substituted. AsR
AsR
NHCOXHz
NH-CO-NH
Carbarsone type ( A )
AsR
T y p e (B)
the use of a liquid liver-proteose-peptone medium. Readings were made 48 hours after introduction of the drug. Carbarsone in this test showed an activity a t 1:20,000 dilution. The comparative activities of the series of compounds is shown in Table I and the biological data will be published elsewhere. Experimental
These compounds were prepared by the reaction Procedure A. Method of Preparation of Arsonic Acid of phosgene with the corresponding arsonoaniline (I) and Arsonoso Compounds I1 and 111.-The procedure and arsonosoaniline in an aqueous alkaline solu- was essentially t h a t of King and Murch.4 The product was b y t h e reprecipitation of the acid from a filtered tion, except compounds VI, XI and XII. An purified alkaline solution. T h e material was washed on the filter aqueous solution of 3-amino-4-hydroxyphenyldi-with two 200-cc. portions of hot water. T h e purified prodchloroarsine hydrochloride was used in the synthe- uct was dried in a vacuum oven a t 60’. The starting material for the preparation of I1 and 111 was sis of VI. Compound XI was obtained by the reand m-arsonosoaniline.6 duction of the corresponding arsonic acid using p-arsonosoaniline6 Procedure B. Method of Preparation of Arsonoso phosphorus trichloride in ethyl acetate. Compound Compounds V, VI and Arsonic Acid (IV). N,N‘-Bis-(5arsonoso-2-hydroxyphenyl)-urea (VI) .-The procedure was XI1 was prepared from p-arsonobenzylamine. The arsenic and nitrogen analyses on compounds essentially t h a t of King.’ A solution of the dichloroarsine hydrochloride* in 250 cc. of water was cooled t o 10-15’. 11, V and VI indicated the presence of two moles of A slow stream of phosgene was introduced below the surface water which could not be determined by loss on of t h e stirred solution for about two hours. The foaming drying or by the Karl Fischer method. Therefore was controlled by the addition of a few milliliters of benzene the arsenious acid [-As(OH)~]structure is proposed or toluene, or by intermittent gassing. The white solid, which separated during the gassing, was for these products. -4nalyses of compounds 111, dissolved by making the reaction mixture strongly alkaline XI and XI1 indicated the presence of only one mole- with sodium hydroxide solution. T h e alkaline solution was cule of water which also could not be determined. A extracted with ether, if necessary, t o remove the benzene or toluene, and t h e aqueous phase filtered t o remove any possible structure
is proposed to explain this fact. The arsonoso compounds 11, V and VI were suspended in water and refluxed with an excess of thioglycolic acid to yield the N,N’-carbonyl-bis(substituted phenylarsylenedithi0)-diacetic acids, VII, VI11 and IX, respectively. The compounds were screened against Endameba histolytica, N.R.S. strain, using a modification of the Bradin and Hansen r n e t h ~ d . ~ This involved
insoluble material. By treating the clear filtrate with a saturated solution of ammonium chloride, a precipitate separated which was isolated by filtration. This solid was slurried with water, then separated by filtration, and washed on the filter until the filtrate gave no test for chlorides with silver nitrate solution. The product was dried in a vacuum oven at 60”. N,N’-Bis-(5-arsono-2-chlorophenyl)-urea (IV) and N,N’Bis-( 5-arsonoso-2-chlorophenyl)-urea (V) .-The procedure for the preparation of these compounds was the same as for compound V I using a dilute alkaline solution as the reaction solvent. The products were precipitated from t h e alkaline solution b y the addition of concentrated hydrochloric acid. N,N’-Bis-(9-arsonopheny1)-thiourea(X) .-Procedure A was followed using an equivalent amount of thiophosgene. T h e product was isolated and purified in the same manner. Anal. Calcd. for C I ~ H I ~ A S Z N Z O As, ~ S31.47; : N , 5.88. Found: As, 31.45; N, 5.71.
(1) Presented at the 125th meeting of the American Chemical Society, Division of Medicinal Chemistry, at Kansas City, March, 1954. ( 2 ) H. H. Anderson, E . L. Hansen, P. P. T. Sah and J. R . Cafiso, J . Pharmacol. Exptl. Therap., 91, 112 (1947); H . H. Anderson, H. G. Johnstone and E. L. Hansen, A m . J . Trop. M e d . , 27, 153 (1947); H . H. Anderson, H . G. Johnstone. W. Bostick. A. P. Chevarria and II. Packer, J . A m . M e d . Assoc.. 140, 1251 (1’349). (3) J. L. Bradin and E. L. Hansen, A m . J . T r o p . M c d . , SO, 27 (1950).
(4) H. King and W. 0. Murch, J . Chem. Soc., 2.595 (1924). (5) A. J. Quick and R . Adams, THISJOURNAL, 44, SO5 (1922). (6) C. S. Hamilton and J . F . Morgan, in “Organic Reactions,” Vol. 11, John Wiley and Sons, Inc., New York, 1944, p. 425; G. 0. Doak, H. Eagle and H. S. Steinman, THISJOURNAL, 62, 168 (1940). (7) H . King, J . Chem. Soc., 1049 (1927). (8) A. B. Scott, R . D . Hummel, B. F. Lullar and J. Wainwright, U. S. Patent 2,221,817 (1840).
\V. D. KRUEGER, L. W. CLEMENCE AND M. T. LEFFLER
4930
TABLE Io
rxn
ARSENICSUBSTITUTED DIPHENYLUREAS
P
NO.
I I1 111 IV
Y 1-I
Procedure
H H
A A
H 2-c1
.4 I3
2-c1 2-OH
B B
Formula
C1$H14ASZ1\T20$
o
Analyses, 70 Arsenic Sitrogen Calcd. Found Calcd. Found
32.56 34.99 C1aHi?As?NzOa 36.54 C I ~ H ~ ~ A S ~ C ~ ~ X ~26.52 O, C~~H~?-~S?CI~?*TZO~ 30.15 32.56 CI~HII~~S~A-~O ~ C1ZH14AszXa0.i
L
Vol. 76
32.30 35.02 36 49 26.76 30.75 33.33
6.09 6.54 6.83 4.96 5.64 6.09
6.03 6.53 6.72 4.75 5.35 5.80
I1
1-11 SCH2COOI-I(Sa) 1.111 3As&H~COOH(
"e1
1 : 50,000 1 : 50,000 1 : 10,000 Inactive 1 : 100,000
I : 2Ull. 000 1 :2 )OO
C ~ l ~ ~ Z a ~ ~ s r C 1 ~ N z O s16.49' S 4 ( 4 S a )17.02
3. 18b
3.15
1: l O , ( i ~ I ! l
Sa)
SCHZCOOH
1:21 Nl , o Y)
2-OH
IX
Activity E . hisl.
2COOH 011heating t o 300", all of these compounds charred without melting. structure is the postulated anhydride, see text.
Anhydride of N,N'-Bis-(9-arsonosopheny1)-thiourea(XI). -The procedure is essentially t h a t of Ehrlich and Bertheim.0 T h e sym-diphenylthioureadiarsonicacid was suspended in dry ethyl acetate and an excess of phosphorus trichloride was added dropwise with vigorous shaking. T h e mixture warmed u p and the solid gradually went into solution. The solution was filtered t o remove any insoluble material and t h e clear filtrate was shakeii with an excess of concentrated ammonium hydroxide whereupon a white product separated, which was isolated by filtration. T h e solution obtained by dissolving the precipitate in 10% sodium hydroxide solution was filtered and the product reprecipitated by adding an excess of saturated ammonium chloride solution. T h e solid was washed with mater until the filtrate gave a negative chloride test and was then dried in a vacuum oven at 60". Anal. Calcd. for C I ~ H L ~ A S ~ As, X~O 35.16; ~: N, 6.58. Found: As, 35.19;N, 6.68. Anhydride of N,N'-Bis-(p-arsonosobenzy1)-urea (XII) .T h e p-arsonosobenzylamine was prepared using the proccdure of Fox,'O and was treated with phosgene using procedure A . The crude product was precipitated from an alkaline solution with a saturated solution of ammonium chloride. The solid product \\as isolated by filtration and washed on the filter until the silver nitrate test of the filtrate was negative. The product was dried in a vacuum oven a t 60". A n d . Calcd. for Ci5Ht6As2N2O4: As, 34.20; N, 6.40. Found: iis, 33.96;S, 6.44.
Calculated as the tetrasodium salt.
Thi,
of water was treated with 46 g. (0.5 mole) of thioglycolic acid. The mixture was refluxed until all of the solid diisolved. The clear hot solution was filtered and allowed t o cool slowly. The oil, which separated, solidified on further cooling in an ice-bath. The solid was broken up and isolated by filtration. T h e crude product was dissolved in 100 cc. of ethanol, treated with charcoal and filtered. The clear filtrate was diluted with 1.5 liters of warin water and the clear solutiou cooled in an ice-bath. The white solid, which slowly sepnrated, was isolated by filtration and dried in a vacuum oven a t 60". Tetrasodium N,N'-Carbonyl-bis-(4-sminophenylarsylenedithio)-diacetate (VII) and Tetrasodium N,N'-Carbonylbis - (3- amino - 4 - chlorophenylarsylenedithio) - diacetate (VIII) .-A sus2ension of 0.1 mole of the arsonoso compound iii 500 cc. of water was refluxed with 0.5mole of thiogl3,collic acid for 15 minutes. The mixture was cooled a n d the aqueous layer decanted from the oily layer. The oil \vas dissolved in a minimum quantity of 107, sotliuni hydroxide solution, treated with charcoal and filtered. Thc clear filtrate was treated with a large excess of ethanol. The water-alcohol layer was decanted from the gummy solid which formef. The gummy product was refluxed 15 miiiutes with 213 cc. of ethanol. On cooling the mixture the insoluble prxluct solidified and wvas isolated by filtration and dried in a vacuum oveii a t DO'.
Acknowledgment.-The authors wish to thank N r . E. F. Shelberg and the microanalytical staff N ,N'-Carbonyl-bis-(3-amino-4-hydroxyphenylarsylenedi- for the microanalyses and Mr. C. J. Rickher and thio)-diacetic Acid (IX) .-A suspension of 42.4 g. (0.1 mole) XLIiss Daisy Herman for the i n m h o amebacidal of i\;,l\;'-bis-(5-arsonoso-2-h~-droxyphenyl)-urea in 500 cc. tests. (9) P. Ehrlich and A . Bertheim, Be?., 43, 917 (1910). (10) H.13. Fox, J . O i g . Chcin , 13, 438 (1048).
NORTHCHICAGO, ILLINOIS
